Current Management of Opioid-Related Side Effects

Current Management of Opioid-Related Side Effects

The management of opioid-related side effects in advanced
cancer patients remains a challenge, and the problems involved are well described
by O’Mahony et al in their article. The authors provide us with an excellent
review of the current literature and, based also on their own experience, offer
recommendations for dealing with opioid-related side effects. We strongly concur
with the points presented by Dr. O’Mahony and his colleagues. In the following
comments, we will emphasize a number of important issues sometimes overlooked in
clinical practice, and will provide examples of our approach to managing adverse
effects in the McGill Palliative Care Program.

Many of the common side effects of opioids are also common
symptoms caused by the underlying cancer. In an attempt to simplify this complex
situation, it is useful to distinguish the well-recognized adverse effects, such
as nausea, vomiting, constipation, drowsiness, and respiratory depression, from
the less well-recognized neuropsychiatric adverse effects, such as myoclonus,
hallucinations, cognitive failure, delusion, and delirium. The well-recognized
side effects usually occur at the start of the opioid regimen and/or with
incremental doses; the neuropsychiatric adverse effects are more frequently
related to long-term use, high-doses, and general metabolic abnormalities
(notably, renal disease).

Evaluating Symptoms

Nausea, vomiting, drowsiness, and respiratory depression tend to
resolve quickly after the initiation and titration of opioid analgesia; however,
tolerance to constipation does not. We recommend evaluating symptoms using a
visual analog or categorical scale prior to initiating therapy with an opioid
analgesic medication and documenting the effects on the chart. Too often,
patients are not asked before starting opioids if they are experiencing
gastrointestinal symptoms, and the addition of an opioid may then exacerbate a
previously tolerable gastrointestinal problem. Consequently, a patient’s
nausea and vomiting may increase, and the patient may undergo unnecessary
studies.

For patients seen in the outpatient clinic, we usually prescribe
an antiemetic to be used as needed. Because gastroparesis is common in advanced
cancer patients,[1] we feel that the antiemetic metoclopramide is probably the
best choice. A placebo-controlled trial has shown metoclopramide to be effective
in this patient population.[2] Of note, metoclopramide, like haloperidol, can be
administered subcutaneously every 4 hours or in a continuous infusion over 24
hours.[3] The usual recommended dose is 60 mg in 24 hours, although higher doses
may be required. When nausea and vomiting persist for more than a week after
initiation of opioid therapy, another cause should be investigated.

Constipation and
Nausea and Vomiting

The most common cause of nausea and vomiting with chronic use of
opioids is probably underrecognized constipation. The authors present
the standard definition of constipation; however, this definition has many
limitations. It is probably more reasonable to look for a change in the bowel
habits of cancer patients taking opioids. Noteworthy signs include decreased
frequency or increased difficulty passing stool. Because constipation remains
difficult to assess, we usually perform an abdominal x-ray when we are unsure of
the degree of stool retention.

Starreveld et al described a very simple scoring system for
evaluating constipation. The colon is divided into four segments, with a score
of 0 to 3 assigned to each segment for a possible total score of 12.[4] The
patient who presents with a score higher than 7 should be considered constipated
and requires more aggressive assessment. The main limitation of this scoring
system is that a patient may have a score lower than 7 and yet have a large
fecaloma limited to one segment. Such patients also need an increased bowel
regimen to alleviate the risk of a stool-induced intestinal blockage.

Undeniably, the best approach to constipation is prevention.
Patients with advanced cancer have a propensity for developing constipation, and
in the absence of a contraindication, we usually start therapy with sodium
docusate and senna. A clinical nurse specialist instructs patients on how to
adjust the dose according to their bowel habits. The use of psyllium remains
risky because cancer patients may have difficulty drinking enough fluid to make
this medication effective, and in some situations, this may lead to increased
constipation.

Respiratory Depression

As well described in the article by O’Mahony et al,
respiratory depression remains a transitory problem following the initiation of
opioids, and tolerance develops rapidly. The risk of respiratory depression,
however, may recur when patients are switched from one opioid to another or from
the oral route to the parenteral route. In the latter case, mistakes may occur
because of a lack of understanding of equianalgesia as well as partial
cross-tolerance of the opioids.

Physicians must familiarize themselves with published opioid
equivalency tables.[5] These are useful guides, although individual patient
variation is common and some tables are misleading with respect to methadone. Of
note, dangerous respiratory depression often develops when patients are switched
from high-dose opioids to methadone. This is especially important because many
published tables suggest that morphine and methadone are equianalgesics when, in
fact, the analgesic ratio of these agents more likely exceeds 10:1.[6] Methadone
is an inexpensive analgesic with inhibitory NMDA effects and exhibits limited
cross tolerance with other opioids. We anticipate that it will be a widely used
opioid in the future. Clinicians should be trained in its use.[7]

Cognitive Failure

While drowsiness is common at the start of opioid treatment and
usually resolves, true cognitive failurea component of deliriumis very
common in advanced cancer and almost the rule at the end of life.[8] Delirium in
advanced cancer patients is characterized by an acute onset of cognitive
failure, hallucinations, delusions, sleep-awake cycle reversal, psychomotor
retardation, and/or agitation.

Physicians caring for advanced cancer patients should actively
look for the onset of cognitive failure using objective testing such as the
Folstein Mini-Mental Status Questionnaire.[9] This test is only a rough guide,
and patients at risk should be asked regularly if they are experiencing
hallucinations (visual or tactile), delusions (mainly paranoia), insomnia, or
fearful nightmares. When the patient’s clinical picture meets DSM-IV criteria,
the diagnosis of delirium should be recorded on the chart.[10] Delirium requires
a prompt, complete investigation to rule out such causes as sepsis, liver and
renal failure, hypoxia, hypercalcemia, and dehydration. Reversible etiologies
should be treated.

In some patients, dehydration associated with renal failure
results in drug accumulation, including opioids and their metabolites. Adverse
drug effects are among the principle causes of delirium. Simple measures to
manage this situation include reducing the opioid dose or switching opioids,
initiating moderate hydration (1,000 to 1,500 mL of normal saline per 24 hours),
and discontinuing other potentiating drugs.[8] Patients should also be treated
symptomatically using neuroleptics (eg, haloperidol, methotrimeprazine) when
delirium is irreversible and death is soon anticipated, benzodiozephines such as
midazolam may also be employed.